Multiplexed assays reveal effects of missense variants in MSH2 and cancer predisposition
Sofie V. Nielsen, Rasmus Hartmann‐Petersen, Amelie Stein, Kresten Lindorff‐Larsen
Abstract
DNA sequencing plays an increasingly central role in clinical research and diagnostics. Genome-wide association studies have established many links between genes and disease but do not reveal the effect of most of the many possible variants within each disease-related gene. Thus, while the explosion in sequencing of human genomes has revealed millions of missense variants that change protein sequences, we only understand the phenotypic and clinical consequences of a minute fraction of these. This lack of knowledge has direct consequences for clinical action. Even if a variant is discovered in a known disease-related gene, most variants have the status of "unknown significance" (VUS) simply because they have not been encountered before in the population or been studied in the laboratory.